1sse
From Proteopedia
Solution structure of the oxidized form of the Yap1 redox domain
Structural highlights
Function[YAP1_YEAST] Transcription activator involved in oxidative stress response and redox homeostasis. Regulates the transcription of genes encoding antioxidant enzymes and components of the cellular thiol-reducing pathways, including the thioredoxin system (TRX2, TRR1), the glutaredoxin system (GSH1, GLR1), superoxide dismutase (SOD1, SOD2), glutathione peroxidase (GPX2), and thiol-specific peroxidases (TSA1, AHP1). The induction of some of these genes requires the cooperative action of both, YAP1 and SKN7. YAP1 preferentially binds to promoters with the core binding site 5'-TTA[CG]TAA-3'. Activity of YAP1 is controlled through oxidation of specific cysteine residues resulting in the alteration of its subcellular location. Oxidative stress (as well as carbon stress, but not increased temperature, acidic pH, or ionic stress) induces nuclear accumulation and as a result YAP1 transcriptional activity. Nuclear export is restored when disulfide bonds are reduced by thioredoxin (TRX2), whose expression is controlled by YAP1, providing a mechanism for negative autoregulation. When overexpressed, YAP1 confers pleiotropic drug-resistance and increases cellular tolerance to cadmium, iron chelators and zinc.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe ability of organisms to alter their gene expression patterns in response to environmental changes is essential for viability. A central regulator of the response to oxidative stress in Saccharomyces cerevisiae is the Yap1 transcription factor. Upon activation by increased levels of reactive oxygen species, Yap1 rapidly redistributes to the nucleus where it regulates the expression of up to 70 genes. Here we identify a redox-regulated domain of Yap1 and determine its high-resolution solution structure. In the active oxidized form, a nuclear export signal (NES) in the carboxy-terminal cysteine-rich domain is masked by disulphide-bond-mediated interactions with a conserved amino-terminal alpha-helix. Point mutations that weaken the hydrophobic interactions between the N-terminal alpha-helix and the C-terminal NES-containing domain abolished redox-regulated changes in subcellular localization of Yap1. Upon reduction of the disulphide bonds, Yap1 undergoes a change to an unstructured conformation that exposes the NES and allows redistribution to the cytoplasm. These results reveal the structural basis of redox-dependent Yap1 localization and provide a previously unknown mechanism of transcription factor regulation by reversible intramolecular disulphide bond formation. Structural basis for redox regulation of Yap1 transcription factor localization.,Wood MJ, Storz G, Tjandra N Nature. 2004 Aug 19;430(7002):917-21. PMID:15318225[14] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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